Abstract
Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p <.05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p <.002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p <.001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p <.05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 745-759 |
| Number of pages | 15 |
| Journal | Stem cells translational medicine |
| Volume | 3 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- Cell migration
- Cell signaling
- Mesenchymal stem cells
- Stem cell-microenvironment interactions
- Tissue regeneration
ASJC Scopus subject areas
- Cell Biology
- Developmental Biology
Cite this
Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes : A recipe for impaired wound healing. / Dasu, Mohan R.; Ramirez, Sandra R.; La, Thi Dinh; Gorouhi, Farzam; Nguyen, Chuong; Lin, Benjamin R.; Mashburn, Chelcy; Stewart, Heather; Peavy, Thomas R.; Nolta, Jan; Isseroff, Roslyn Rivkah.
In: Stem cells translational medicine, Vol. 3, No. 6, 2014, p. 745-759.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes
T2 - A recipe for impaired wound healing
AU - Dasu, Mohan R.
AU - Ramirez, Sandra R.
AU - La, Thi Dinh
AU - Gorouhi, Farzam
AU - Nguyen, Chuong
AU - Lin, Benjamin R.
AU - Mashburn, Chelcy
AU - Stewart, Heather
AU - Peavy, Thomas R.
AU - Nolta, Jan
AU - Isseroff, Roslyn Rivkah
PY - 2014
Y1 - 2014
N2 - Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p <.05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p <.002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p <.001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p <.05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs.
AB - Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p <.05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased β2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), β2-AR protein (2.5-fold), phosphorylation of β-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased β2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p <.002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p <.001) responses that were remarkably reduced by pretreatment with β2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p <.05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs.
KW - Cell migration
KW - Cell signaling
KW - Mesenchymal stem cells
KW - Stem cell-microenvironment interactions
KW - Tissue regeneration
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U2 - 10.5966/sctm.2013-0200
DO - 10.5966/sctm.2013-0200
M3 - Article
VL - 3
SP - 745
EP - 759
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 6
ER -